Summary:
Human African Trypanosomiasis (HAT) or sleeping sickness, as it is also known, is a vector borne-parasitic disease, resulting from infections with flagellated unicellular parasites of the species T. brucei. Approximately, 65 million people in 36 countries in sub-Saharan Africa are at risk of infection, and HAT has been recognized by World Health Organization as a Neglected Tropical Disease. Nowadays, only a few clinically useful drugs are available which suffer from severe side effects. The situation is aggravated by the alarming increased incidence of treatment failure in conjunction with the development of resistance against current chemotherapy and the inability of vaccination due to antigenic variation. HAT draws the attention of WHO, which aims to eliminate the disease and implements sustained surveillance in all countries. Thus, the research has been focused on the discovery of new drugs and the identification of new drug-targets in T. brucei.
Based on previous findings, according to which spiro carbocyclic derivatives of 2,6-diketopiperazine core with the incorporation of the acetohydroxamic group at the imidic nitrogen showed high potency against T. brucei, a series of novel compounds were designed, synthesized and evaluated for their trypanocidal activity. The new analogues were derived from the replacement of the 2,6-diketopiperazine ring by the 2,4-diketoimidazolidine scaffold, also known as hydantoin, attached by the acetohydroxamic acid moiety at the imidic nitrogen, which acts a metal ion chelating functional group of T. brucei metalloenzymes. Hydroxamic acids bind bidentately with the M2+ ion to the catalytic site of metalloproteins. The acetohydroxamate acid moiety coordinates through the carbonyl oxygen and the deprotonated hydroxyl oxygen with the M2+. Metalloproteins are enzymes that contain metal ions as cofactors and serve as regulators of a wide range of functions, including antioxidant metabolism, glycolysis, DNA transcription and DNA repair. Given the importance of these metalloenzymes for the survival of T. brucei, their inhibition offers an attractive approach to HAT treatment. A variety of lipophilic carbocyclic rings have been used as spiro substituents at position 5, in order to increase the affinity for the target through Van der Waals and hydrophobic interactions. A further structural modification was accomplished by attaching an additional methyl group at the amidic nitrogen, so as to increase the binding capacity of the derivatives.
The new compounds exhibited considerable potent activity against T. brucei with IC50 values in low nanomolar range. The cytotoxicity of the newly synthesized analogues was extremely small for mammalian cells and the selectivity indices were significantly high. The derivative substituted with the fluoerene core and the additional methyl moiety was the most potent with a notable selectivity index. The incorporation of a methyl group at the amidic nitrogen, led to an increased activity for almost all compounds. Interestingly, it was observed a positive correlation between lipophilicity and trypanocidal activity, and consequently, bulky and lipophilic substituents seem to be favorable.
In conclusion, the design and synthesis of new analogues that bear a suitable group, capable of chelating metal ions in the catalytic site of metalloenzymes, is a promising field in drug discovery for the treatment of HAT. Τhe novel 2,5-spiro carbocyclic diketoimidazolidine scaffold emerge as valuable platform either for the development of antitrypanosomal agents or agents against other diseases by introducing an appropriate substituent.
